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  • Title: Increased protein kinase C delta in mammary tumor cells: relationship to transformtion and metastatic progression.
    Author: Kiley SC, Clark KJ, Duddy SK, Welch DR, Jaken S.
    Journal: Oncogene; 1999 Nov 18; 18(48):6748-57. PubMed ID: 10597283.
    Abstract:
    Relatively little is known about the molecular mechanisms of tumor promotion/progression in mammary carcinogenesis. Increased protein kinase C (PKC) activity is known to promote tumor formation in several tissues; however, its role in mammary carcinogenesis is not yet known. To determine if individual PKCs may selectively regulate properties of mammary tumor cells, we compared PKC isozyme levels in mammary tumor cell lines with low, moderate and high metastatic potential. All three cell lines expressed alpha, delta, epsilon and zeta PKCs; however, PKC delta levels were relatively increased in the highly metastatic cells. To determine if increased PKC delta could contribute to promotion/progression, we overexpressed PKC delta in the low and moderately metastatic cell lines. PKC delta overexpression had no significant effect on growth of adherent cells, but significantly increased anchorage-independent growth. Conversely, expressing the regulatory domain of PKC delta (RD delta), a putative PKC delta inhibitory fragment, inhibited anchorage-independent growth. The efficacy of RD delta as a PKC delta inhibitor was demonstrated by showing that RD delta selectively interfered with PKC delta subcellular location and significantly interfered with phosphorylation of the PKC cytoskeletal substrate, adducin. PKC-dependent phosphorylation of cytoskeletal substrate proteins, such as adducin, provides a mechanistic link between increased PKC delta activity and phenotypic changes in cytoskeletal-dependent processes such as migration and attachment, two processes that are relevant to metastatic potential. The reciprocal growth effects of expressing PKC delta and RD delta as gain and loss of function constructs, respectively, provide strong evidence that PKC delta regulates processes important for anchorage-independent growth in these mammary tumor cells.
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